VOQUEZNA

1 INDICATIONS AND USAGE VOQUEZNA is indicated: for healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults. to maintain healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults. for the relief of heartburn associated with non-erosive gastroesophageal reflux disease in adults. in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori ( H. pylori ) infection in adults. in combination with amoxicillin for the treatment of H. pylori infection in adults. VOQUEZNA is a potassium-competitive acid blocker indicated: for healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults. ( 1 ) to maintain healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults. ( 1 ) for the relief of heartburn associated with non-erosive gastroesophageal reflux disease in adults. ( 1 ) in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection in adults. ( 1 ) in combination with amoxicillin for the treatment of H. pylori infection in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage : Healing of Erosive Esophagitis: 20 mg once daily for 8 weeks. ( 2.1 ) Maintenance of Healed Erosive Esophagitis: 10 mg once daily for up to 6 months. ( 2.1 ) Relief of Heartburn Associated with Non-Erosive Gastroesophageal Reflux Disease: 10 mg once daily for 4 weeks. ( 2.1 ) Treatment of H. pylori Infection: see full prescribing information. ( 2.1 ) See also full prescribing information for the recommended dosage by indication for patients with renal or hepatic impairment. ( 2.2 , 2.3 ) Administration Instructions : Take with or without food. ( 2.4 ) Swallow whole; do not chew or crush. ( 2.4 ) 2.1 Recommended Dosage Healing of Erosive Esophagitis The recommended adult oral dosage is VOQUEZNA 20 mg once daily for 8 weeks for the treatment of healing of erosive esophagitis and relief of associated heartburn. Maintenance of Healed Erosive Esophagitis The recommended adult oral dosage is VOQUEZNA 10 mg once daily for up to 6 months for the maintenance of healed erosive esophagitis and relief of associated heartburn. Relief of Heartburn Associated with Non-Erosive Gastroesophageal Reflux Disease The recommended adult oral dosage is VOQUEZNA 10 mg once daily for 4 weeks. Treatment of H. pylori Infection Triple Therapy: The recommended adult oral dosage is VOQUEZNA 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (in the morning and evening, 12 hours apart) for 14 days. Dual Therapy: The recommended adult oral dose is VOQUEZNA 20 mg given twice daily (in the morning and evening) plus amoxicillin 1,000 mg three times daily (in the morning, mid-day, and evening) for 14 days. Also refer to the amoxicillin and clarithromycin full prescribing information. 2.2 Recommended Dosage in Patients with Renal Impairment Healing of Erosive Esophagitis The recommended dosage of VOQUEZNA in adult patients with renal impairment is described in Table 1 below [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Table 1: Recommended VOQUEZNA Dosage in Patients with Renal Impairment: Healing of Erosive Esophagitis Estimated glomerular filtration rate (GFR) Recommended Dosage 30 mL/minute or greater 20 mg once daily Less than 30 mL/minute 10 mg once daily Maintenance of Healed Erosive Esophagitis or Relief of Heartburn Associated with Non-Erosive Gastroesophageal Reflux Disease The recommended dosage of VOQUEZNA in adult patients with renal impairment is the same as for adult patients with normal renal function [see Dosage and Administration (2.1) ] . Treatment of H. pylori Infection The recommended dosage of VOQUEZNA in adult patients with renal impairment is described in Table 2 below [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. Table 2: Recommended VOQUEZNA Dosage in Patients with Renal Impairment: Treatment of H. pylori Infection Also refer to the Dosage and Administration section of the amoxicillin and clarithromycin prescribing information for dosage recommendations in patients with renal impairment. Estimated GFR Recommended Dosage 30 mL/minute or greater 20 mg twice daily Less than 30 mL/minute Use is not recommended 2.3 Recommended Dosage in Patients with Hepatic Impairment Healing of Erosive Esophagitis The recommended dosage of VOQUEZNA in adult patients with hepatic impairment is described in Table 3 below [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Table 3: Recommended VOQUEZNA Dosage in Patients with Hepatic Impairment: Healing of Erosive Esophagitis Classification Recommended Dosage Child-Pugh Class A 20 mg once daily Child-Pugh Class B 10 mg once daily Child-Pugh Class C 10 mg once daily Maintenance of Healed Erosive Esophagitis or Relief of Heartburn Associated with Non-Erosive Gastroesophageal Reflux Disease The recommended dosage of VOQUEZNA in adult patients with hepatic impairment is the same as for patients with normal hepatic function [see Dosage and Administration (…

5 WARNINGS AND PRECAUTIONS Gastric Malignancy : Symptomatic response to treatment does not preclude the presence of gastric malignancy; consider additional follow-up and diagnostic testing. ( 5.1 ) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.2 ) Clostridioides difficile -Associated Diarrhea (CDAD) : May be associated with an increased risk; use the shortest duration of treatment appropriate to the condition. ( 5.3 ) Bone Fracture, including Osteoporosis-related Fracture : Use the shortest duration of treatment appropriate to the condition. ( 5.4 ) Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) Vitamin B12 (Cobalamin) Deficiency : Long-term use may lead to malabsorption or deficiency; consider further workup if clinical symptoms are present. ( 5.6 ) Hypomagnesemia and Mineral Metabolism : Hypomagnesemia may lead to hypocalcemia and/or hypokalemia. Consider monitoring magnesium and calcium levels in at-risk patients, or if there is concomitant use of digoxin or other drugs that cause hypomagnesemia. ( 5.7 ) Interactions with Investigations for Neuroendocrine Tumors : Increased chromogranin A (CgA) levels may interfere with diagnostic investigations; temporarily stop VOQUEZNA at least 4 weeks before assessing CgA levels. ( 5.8 , 7 ) Fundic Gland Polyps : Risk increases with long-term use; use the shortest duration of treatment appropriate to the condition. ( 5.9 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with VOQUEZNA does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in patients who have a suboptimal response or an early symptomatic relapse after completing treatment with VOQUEZNA. In older patients, also consider endoscopy. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been reported with VOQUEZNA [see Adverse Reactions (6.1) ] . If suspected, discontinue VOQUEZNA and evaluate patients with suspected acute TIN. 5.3 Clostridioides difficile -Associated Diarrhea Published observational studies suggest that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridioides difficile -associated diarrhea (CDAD), especially in hospitalized patients. VOQUEZNA, another drug that blocks the proton pump to inhibit gastric acid production, may also increase the risk of CDAD. Consider CDAD in patients with diarrhea that does not improve [see Adverse Reactions (6.2) ] . Use the shortest duration of VOQUEZNA appropriate to the condition being treated. CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with VOQUEZNA, refer to the Warnings and Precautions section of the corresponding prescribing information. 5.4 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term therapy (a year or longer). Bone fracture, including osteoporosis-related fracture, has also been reported with vonoprazan. Use the shortest duration of VOQUEZNA appropriate to the condition being treated [see Dosage and Administration (2.1) ]. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines . 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with VOQUEZNA [see Adverse Reactions (6.2) ] . Discontinue VOQUEZNA at the first signs or symptoms of severe cutaneous adverse reactions or…

4 CONTRAINDICATIONS VOQUEZNA is contraindicated in patients with a known hypersensitivity to vonoprazan or any component of VOQUEZNA. Reactions have included anaphylactic shock [see Adverse Reactions (6.2) and Description (11) ] . VOQUEZNA is contraindicated with rilpivirine-containing products [see Drug Interactions (7) ] . For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with VOQUEZNA, refer to the Contraindications section of the corresponding prescribing information. Known hypersensitivity to vonoprazan or any component of VOQUEZNA. ( 4 ) Rilpivirine-containing products. ( 4 , 7 )

7 DRUG INTERACTIONS Table 9 and Table 10 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with VOQUEZNA and instructions for preventing or managing them. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3) ] . Consult the labeling of concomitantly used drugs to obtain further information about interactions with vonoprazan. Table 9: Drug Interactions Affecting Drugs Co-Administered with VOQUEZNA and Interactions with Diagnostics Drugs Dependent on Gastric pH for Absorption Antiretrovirals Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ], which may alter the absorption of antiretroviral drugs, leading to changes in the safety and/or effectiveness. Prevention or Management Rilpivirine-containing products Concomitant use with VOQUEZNA is contraindicated . Atazanavir Avoid concomitant use with VOQUEZNA. Nelfinavir Other antiretrovirals See the prescribing information of other antiretroviral drugs dependent on gastric pH for absorption prior to concomitant use with VOQUEZNA. Other Drugs (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ] , which may decrease the absorption of drugs reducing their effectiveness. Prevention or Management See the prescribing information for other drugs dependent on gastric pH for absorption. Combination Therapy with Clarithromycin and/or Amoxicillin Clinical Effect Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and is contraindicated. Amoxicillin also has drug interactions. Prevention or Management See Contraindications and Warnings and Precautions in the prescribing information for clarithromycin. See Drug Interactions in the prescribing information for amoxicillin. Certain CYP3A Substrates Where Minimal Concentration Changes May Lead to Serious Toxicities Clinical Effect Vonoprazan is a weak CYP3A inhibitor [see Clinical Pharmacology (12.3) ] . Vonoprazan may increase exposure of CYP3A4 substrates, which may increase the risk of adverse reactions related to these substrates. Prevention or Management Frequently monitor concentrations and/or adverse reactions related to the substrate drugs when used with VOQUEZNA. Dosage reduction of substrate drugs may be needed. See prescribing information for the relevant substrate drugs. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol) Clinical Effect Vonoprazan is a CYP2C19 inhibitor [see Clinical Pharmacology (12.3) ] . Vonoprazan may reduce plasma concentrations of the active metabolite of clopidogrel and may cause reduction in platelet inhibition. Vonoprazan may increase exposure of CYP2C19 substrate drugs (e.g., citalopram, cilostazol). Prevention or Management Clopidogrel Carefully monitor the efficacy of clopidogrel and consider alternative anti-platelet therapy. Citalopram and Cilostazol Carefully monitor patients for adverse reactions associated with citalopram and cilostazol. See the prescribing information for dosage adjustments. Chromogranin Test for Neuroendocrine Tumors Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ] , which increases CgA levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors . Prevention or Management Assess CgA levels at least 4 weeks after stopping VOQUEZNA treatment and repeat the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), use the same commercial laboratory for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test C…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VOQUEZNA during pregnancy. Healthcare providers are encouraged to register patients by calling 1-866-609-1612 or visiting https://voqueznapregnancyregistry.com/ . Risk Summary There are no adequate and well-controlled studies of vonoprazan in pregnant women. Available data from pharmacovigilance reports with vonoprazan-containing products used in pregnant women are not sufficient to evaluate for a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In pregnant rats, no adverse effects were noted after oral administration of vonoprazan during organogenesis at approximately 27-times the maximum recommended human dose (MRHD), based on AUC exposure comparisons. In a pre- and postnatal development (PPND) study, pups from dams orally administered vonoprazan during organogenesis and through lactation exhibited liver discoloration, which, in follow-up mechanistic animal studies, was associated with necrosis, fibrosis, and hemorrhage at a dose approximately 22-times the MRHD, based on AUC comparisons that were likely attributable to exposure during lactation [see Use in Specific Populations (8.2) ] . These effects were not observed at the next lower dose in this study, which was approximately equal to the MRHD, based on AUC comparison; however, they were seen at clinically relevant exposures in dose range-finding studies in rats (see Data) . The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Pregnant rats were orally administered vonoprazan at doses of 30, 100, or 300 mg/kg/day (7-, 27-, 130-times the MRHD based on AUC comparison at the same doses from unmated female rats from separate studies) during the period of organogenesis from gestation day (GD) 6 to 17. During maternal dosing, one high-dose female died and decreased body weight and food consumption occurred at the middle and highest doses. No embryo-fetal lethality was observed but decreased fetal body weight was observed in the highest dose group. Fetal abnormalities were limited to the 300 mg/kg/day and included ventricular septal defect and mal-positioned subclavian artery in fetuses in a majority (15/19) of litters, as well as tail abnormalities and small anal opening. No adverse embryo-fetal effects were observed at the 100 mg/kg/day. Pregnant rabbits were orally administered vonoprazan at doses of 3, 10, or 30 mg/kg/day (0.04-, 1.5-, 10-times the MRHD based on AUC comparison) during the period of organogenesis from GD 6 to 18. Two animals aborted at the highest dose and decreased body weight and food consumption occurred at the mid and high doses. No embryo-fetal mortality or toxicity occurred. There were no external, visceral, or skeletal abnormalities. In a PPND study, pregnant female rats were orally administered vonoprazan at doses of 1, 3, 10, or 100 mg/kg/day (0.01-, 0.18-, 1.1-, 22-times the MRHD based on AUC comparison) from GD 6 to lactation day (LD) 21. Decreased body weight gain and food consumption were present in dams at the highest dose during lactation. Decreased body weight gain compared to controls was observed in the offspring from dams in the high dose group. Liver discoloration occurred in offspring from the high dose group at LD 4 but was not present in animals examined after weaning. Similarly, in dose range-finding studies in rats and follow-up mechanistic animal studies, the liver discoloration was observed and characterized as necrosis, fibrosis, and hemorrhage at equal to or greater than clinically relevant exposures based …

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.3) ] Bone Fracture [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Vitamin B12 (Cobalamin) Deficiency [see Warnings and Precautions (5.6) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.7) ] Fundic Gland Polyps [see Warnings and Precautions (5.9) ] Most common adverse reactions in VOQUEZNA-treated patients are: Healing of Erosive Esophagitis (≥2%): gastritis, diarrhea, abdominal distension, abdominal pain, and nausea. ( 6.1 ) Maintenance of Healed Erosive Esophagitis (≥3%): gastritis, abdominal pain, dyspepsia, hypertension, and urinary tract infection. ( 6.1 ) Relief of Heartburn Associated with Non-Erosive Gastroesophageal Reflux Disease (≥2%): abdominal pain, constipation, diarrhea, nausea, and urinary tract infection. ( 6.1 ) Treatment of H. pylori Infection (≥2%): diarrhea, dysgeusia, vulvovaginal candidiasis, abdominal pain, headache, hypertension, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Phathom Pharmaceuticals, Inc. at toll-free phone 1-888-775-7428 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Healing of Erosive Esophagitis and Maintenance of Healed Erosive Esophagitis The safety of VOQUEZNA was evaluated in a randomized, active-controlled, double-blind two phase trial for the healing of erosive esophagitis (2 to 8 weeks) and maintenance of healed erosive esophagitis (through 24 weeks) conducted in the United States and Europe [see Clinical Studies (14.1) , (14.2) ] . Adverse reactions reported in at least 2% of patients in the VOQUEZNA 20 mg once daily arm in the healing phase are presented in Table 5 . Table 5: Adverse Reactions Reported in at least 2% of patients in the VOQUEZNA arm. in a Clinical Trial of Adult Patients with All Grades of Erosive Esophagitis The trial was not designed to support comparative claims for VOQUEZNA for the adverse reactions reported in this table. (2 to 8 Week Healing Phase) Adverse Reactions VOQUEZNA 20 mg Once Daily N=514 % Lansoprazole 30 mg Once Daily N=510 % Gastritis Represents a grouped term and includes related terms. 3 2 Diarrhea 2 3 Abdominal distension 2 1 Abdominal pain 2 1 Nausea 2 1 Adverse reactions reported in at least 3% of patients in the VOQUEZNA 10 mg once daily arm of the maintenance phase are shown in Table 6 . Table 6: Adverse Reactions Reported in at least 3% of patients in the VOQUEZNA arm. in a Clinical Trial of Adult Patients with All Grades of Erosive Esophagitis The trial was not designed to support comparative claims for VOQUEZNA for the adverse reactions reported in this table. (24 Week Maintenance Phase) Adverse Reactions VOQUEZNA 10 mg Once Daily N=296 % Lansoprazole 15 mg Once Daily N=297 % Gastritis Represents a grouped term and includes related terms. 6 3 Abdominal pain 4 2 Dyspepsia 4 3 Hypertension 3 2 Urinary tract infection 3 2 COVID-19 COVID-19 was reported in the healing phase in 11 (2%) VOQUEZNA-treated patients and 9 (2%) lansoprazole-treated patients, and in the maintenance phase in 18 (6%) VOQUEZNA-treated patients and 20 (7%) lansoprazole-treated patients. Other Clinical Trials of Erosive Esophagitis Adverse reactions reported in the United States trial were similar to those reported in 4 additional randomized, active-controlled, double-blind studies of vonoprazan compared to lansoprazole conducted outside of the United States (two 8-week trials of healing of erosive esophagitis an…